advances in polyglutamine disease research & therapy albert la spada, m.d., ph.d. professor of...
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Advances in polyglutamine
disease research & therapy
Albert La Spada, M.D., Ph.D.Professor of Pediatrics and Cellular & Molecular Medicine
Division Chief of Genetics, Dept. of PediatricsAssociate Director, Institute for Genomic Medicine
NAF meetingMarch 18, 2011
Advances in molecular genetics fueled a decade (or so) of discovery (1988-2000)
CAG = glutamine (Q)
CAG / polyglutamine repeat diseases
Spinal & bulbar muscular atrophyHuntington’s diseaseDentatorubral pallidoluysian atrophy Spinocerebellar ataxia 1, 2, 3, 6, 7 & 17
all affect the nervous system all are dominant (except SBMA which is X-linked) all comparable median ages of onset all are slowly progressive all show a correlation between increasing expansion size and disease severity - this correlation + tendency of the repeats to expand when transmitted from parent to child explains: ANTICIPATION all are caused exclusively by CAG repeat expansions that are translated into polyglutamine tracts (except SCA6)
SCA7 pedigree (UWMC Neurogenetics Clinic)
d. 16 yo
d. 63 yo
d. 80 yo
38 yo 36 yo
- presented with visual problems at age 6; developed ataxia, went blind, cognitive decline
- dysarthria, ataxia,and central scotoma
48 CAGs
- blind, walks with cane; 50 CAGs
- presented at age 50with visual problems;ataxia / spasticity
- presented with coordination problem in her late 60s
?
Example ofANTICIPATION
= worsening of disease phenotype in
successive generations
...CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG...
DNA sequence = trinucleotide repeat expansion
…QQQQQQQQQQQQQQQQQQQQQQQ...
Amino acid sequence = glutamine tract expansion
Protein product = misfolded conformation
Formation of protein aggregates in neurodegeneration: a common link
Disease Implicated protein Histopathology
CAG / polyQ Various Nuclear inclusions diseases (e.g. HD)
Alzheimer’s dz APP, apoE, others Neurofibrillary tangles & beta-amyloid plaques
Parkinson’s dz synuclein, others Lewy bodies
ALS (Lou Gehrig’s) TDP-43 Bunina bodies
Jacob-Creutzfeldt prion Prions(mad cow disease)
Towards Therapy
Normal cell in the body
DNA (genes)
Messenger RNA
Protein
Cell affected By SCA7
Abnormal DNA
Incorrectmessage
Protein
Toxic
Andrew Fire and Craig Mello won the Nobel Prizein 2006 for their discovery of RNA interference
Andrew Fire
Stanford University
Craig Mello
University of Massachussets
Round wormsPetunias
RNA interference was first discovered in plants and worms
RNA interference targets the messenger
DNA(genes)
Messenger RNA
protein
Interfere
RNA interference is a promising therapy for many different diseases:
1. Huntington’s disease
2. Other degenerative brain disorders
3. Cancer
4. HIV
RNAi as a therapy for SCA7
RNAi
XTrafficking defects
mutant atx7X Therapy
targets inSCA7